Super-oxide dismutase mimetics

ABSTRACT

The present invention relates to compounds which are effective as catalysts for dismutating superoxide and, more particularly, the manganese or iron complexes of substituted, unsaturated heterocyclic 16-membered macrocyclic complexes that catalytically dismutate superoxide. It also relates to methods of using these complexes to reduce the concentration or the effects of superoxide, pharmaceutical compositions comprising these compounds or their metal complexes, and methods of treating conditions associated with excessive superoxide activity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is divisional of prior application Ser. No. 12/740,399,filed Apr. 29, 2010, which is a 371 National based on InternationalApplication No. PCT/US2008/083666, filed on Nov. 14, 2008. Theseapplications claim the benefit of U.S. Provisional Application No.60/988,003, filed Nov. 14, 2007. Each of these applications isincorporated by reference herein in its entirety.

TECHNICAL FIELD

The present invention relates to compounds which are effective ascatalysts for dismutating superoxide and, more particularly, themanganese or iron complexes of substituted, unsaturated heterocyclic16-membered macrocyclic complexes that catalytically dismutatesuperoxide. It also relates to methods of using these complexes toreduce the concentration or the effects of superoxide, and methods oftreating conditions associated with excessive superoxide activity.

BACKGROUND ART

The enzyme superoxide dismutase catalyzes the conversion of superoxideinto oxygen and hydrogen peroxide according to equation (1) (thisprocess is often referred to herein and in the art as dismutation).2O₂ ⁻+2H⁺→O₂+H₂O₂

Reactive oxygen metabolites derived from superoxide have beendemonstrated to contribute to the tissue pathology in a number ofinflammatory diseases and disorders, such as reperfusion injury to theischemic myocardium, inflammatory bowel disease, rheumatoid arthritis,osteoarthritis, atherosclerosis, hypertension, metastasis, psoriasis,organ transplant rejections, radiation-induced injury, asthma,influenza, stroke, burns and trauma. See, for example, Simic, M. G., etal., Oxygen Radicals in Biology and Medicine, BASIC LIFE SCIENCES, Vol.49, Plenum Press, New York and London, 1988; Weiss, J. Cell. Biochem.,1991 Suppl. 15C, 216 Abstract C110 (1991); Petkau, A., Cancer Treat.Rev. 13, 17 (1986); McCord, J. Free Radicals Biol. Med., 2, 307 (1986);and Bannister, J. V., et al., Crit. Rev. Biochem., 22, 111 (1987). Incertain situations, cells are deficient in natural SOD activity; forexample, this may occur as a result of heart attack, organ transplant,and even cancer: cancer cells are often deficient in SOD and can thuspermit superoxide concentrations to rise and can cause injury tosurrounding tissue.

It is also known that superoxide is involved in the breakdown ofendothelium-derived vascular relaxing factor (EDRF), which has beenidentified as nitric oxide (NO), and that EDRF is protected frombreakdown by superoxide dismutase. This suggests a central role foractivated oxygen species derived from superoxide in the pathogenesis ofhypertension, vasospasm, thrombosis and atherosclerosis. See, forexample, Gryglewski, R. J. et al., “Superoxide Anion is Involved in theBreakdown of Endothelium-derived Vascular Relaxing Factor”, Nature, Vol.320, pp. 454-56 (1986) and Palmer, R. M. J. et al., “Nitric OxideRelease Accounts for the Biological Activity of Endothelium DerivedRelaxing Factor”, Nature, Vol. 327, pp. 523-526 (1987).

Clinical trials and animal studies with natural, recombinant andmodified superoxide dismutase enzymes have been completed or are ongoingto demonstrate the therapeutic efficacy of reducing superoxide levels inthe disease states noted above. However, numerous problems have arisenwith the use of the enzymes as potential therapeutic agents, includinglack of oral activity (a common problem with polypeptides), shorthalf-lives in vivo, immunogenicity of nonhuman derived enzymes, and poortissue distribution.

In an effort to overcome the problems associated with superoxidedismutase enzymes, several investigations have been made into the designof non-proteinaceous catalysts for the dismutation of superoxide, andtheir use in various superoxide-related ailments. One group of catalystswhich has been shown to be nearly as effective catalysts as the nativesuperoxide dismutase enzymes are the manganese and iron complexes ofpentaazacyclopentadecane ligands, described in U.S. Pat. Nos. 5,610,293,5,637,578, and 5,874,421. These ligands include apentaazacyclopentadecane macrocycle with various substituents on thecarbons of the macrocycle, or with cyclic or heterocyclic structuresattached to the carbons of the macrocycle. Some of these complexespossess potent catalytic superoxide dismutating activity, and produceanti-inflammatory activity and prevent oxidative damage in vivo. Inaddition, these compounds, which are sometimes referred to as SODmimetics, have been shown to possess analgesic activity and to reduceinflammation and edema in the rat-paw carrageenan hyperalgesia model,see, e.g., U.S. application Ser. No. 09/057,831. Exemplary compounds ofthis type include those shown in FIG. 1.

DISCLOSURE OF THE INVENTION

Applicants have found a new type of macrocyclic ligand that produceshighly stable complexes with certain metals, including Mn and Fe, andprovides improved activity as a SOD mimetic. The new macrocyclic ligandsinclude a conjugated unsaturated 1,5-diaza group that deprotonates toprovide a delocalized anion analogous to an acetylacetonate ligand(AcAc) ligand. This delocalized anionic group is an especially goodbidentate ligand for certain metal cations: its affinity for the metalis increased by the ionic attraction between the anionic ligand and themetal. Applicants have found that incorporating this as part of amacrocyclic ring containing other nitrogen atoms provides SOD mimeticswith especially potent activity. In addition, complexes of these ligandswith a metal are less prone to dissociate at lower pH, possibly becausethe ligand has less tendency to become protonated to an extent thataccelerates dissociation of a complexed metal cation. This five-atomsubunit is incorporated into a 16-membered macrocyclic ring that islarger than the 15-membered rings previously described as SOD mimetics,and it introduces additional conformational control that may helpstabilize the complex. Thus it provides SOD mimetic compounds withimproved characteristics for certain applications.

In one aspect, the invention includes compounds of formula (1):

wherein:

each R¹ is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl,or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl),each of which can be substituted with one or more groups selected fromhalo, ═O, OR, S(O)_(t)R, NR₂, COOR, CONR₂, wherein t can be 0-2 and eachR independently represents H, C1-C4 alkyl, and wherein two R groups onone N can cyclize to form a saturated azacyclic group;

each R² is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl,or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl),each of which can be substituted with one or more groups selected fromhalo, OR, S(O)_(t)R, NR₂, COOR, CONR₂, wherein t can be 0-2 and each Rindependently represents H, C1-C4 alkyl, and wherein two R groups on oneN can cyclize to form a saturated azacyclic group;

each R³ is H or a protecting group;

wherein any two R¹ on a single carbon can cyclize to form a ring having3-8 ring atoms, which ring can be substituted, and which can contain aheteroatom selected from N, O and S as a ring member;

and any two R¹ on adjacent carbon atoms, and any two R² groups onadjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms,which ring can be substituted and can be aromatic or non-aromatic, andcan contain a heteroatom selected from N, O and S as a ring member;

and any two R¹ on carbon atoms separated by a single Nitrogen atom cancyclize to form a ring having 3-8 atoms, which ring can be substitutedand can be aromatic or non-aromatic, and can contain, in addition to theN between the carbon atoms to which linked groups are attached, anadditional heteroatom selected from N, O and S as a ring member;

and any two R² on carbon atoms separated by a single Nitrogen atom cancyclize to form a ring having 3-8 atoms, which ring can be substitutedand can be aromatic or non-aromatic, and can contain, in addition to theN between the carbon atoms to which linked groups are attached, anadditional heteroatom selected from N, O and S as a ring member;

each m is independently 0 or 1;

each n and p is independently 0-2;

L represents a three-atom linker that may be —C(R¹)_(p)—NR³—C(R¹)_(p)—or an optionally substituted pyridine-2,6-diyl group; and

M represents H or a metal cation;

or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a compound of formula (2a):

wherein R¹, R², m, n, p and M are as defined for formula (1).

In another aspect, the invention provides a compound of formula (2b):

wherein R¹, R², m, n, p and M are as defined for formula (1), and R⁴represents one or two optional substituents which may be present at anyposition(s) on the pyridine ring.

In another aspect, the invention provides compounds of formula (3):

wherein R¹, R², R³, L, m, p and M are as defined above for formula (1),and wherein R^(1a) is an optionally substituted alkyl group, and whereintwo R^(1a) groups on adjacent carbons can link to form a ring.

The above compounds may be prepared as pharmaceutically acceptable saltsor as prodrugs. Thus in another aspect, the invention includes theprodrugs of the compounds of formulas (1)-(3) and the pharmaceuticallyacceptable salts of these compounds and prodrugs

As those of ordinary skill will appreciate, compounds of these generalformulae can also be represented by other resonance structures ortautomeric structures wherein the double bonds of the macrocycle offormula (1) are not necessarily localized as shown. Those structures areequivalent for purposes of the invention: one tautomer is often depictedfor convenience only and not to limit the invention. An equallyappropriate way of representing a complex within the scope of theinvention is this:

where M^(m+) represents a metal cation that is bound symmetricallybetween the two nitrogens of the delocalized anionic binding portionshown at the top of the macrocycle, and is concurrently stronglycoordinated to the other three nitrogen atoms in the macrocyclic ring,producing a powerful chelation effect.

These compounds and their pharmaceutically acceptable salts are usefulas mimetics of the enzyme super oxide dismutase (SOD). Therefore, likeSOD, they are useful to treat conditions where excessive superoxide ispresent or is likely to form. However, unlike SOD, the compounds of theinvention are not prone to rapid degradation by proteolysis: they aretherefore better for in vivo applications than SOD, because they tend tobe longer lived and also can be administered orally. Because of theirdifferent structural and charge characteristics, they are often morestable and thus more potent in vivo and more effective upon oraladministration than previously reported SOD mimetics.

In another aspect, the invention provides pharmaceutical compositionscomprising a compound of formula (1), (2a), (2b), or (3) admixed with atleast one pharmaceutically acceptable excipient. These compositions maybe administered to a patient at risk of oxidative injury due toexcessive superoxide formation, either alone or admixed with otheractive ingredients known to be beneficial for such patients, includingdrugs known to slow the formation or accelerate the decomposition ofsuperoxide, and compounds that promote the decomposition of hydrogenperoxide, which is a less harmful but still oxidative material that isproduced when superoxide is degraded by SOD or SOD mimetics. Likewise,the invention also provides methods of using the compounds describedherein for the manufacture of a medicament.

In another aspect, the invention provides a method to reduce theconcentration of destructive oxidative species, especially superoxide,in a locus where such destructive oxidative species are predicted toform. The method involves delivering a compound of formula (1), (2a),(2b), or (3) to the locus where such destructive oxidative species,typically superoxide, exist or are expected to form. This can includedelivering a compound of formula (1), (2a), (2b), or (3) to a patient orapplying it to a tissue, wherein the patient or tissue is at risk ofinjury caused by superoxide.

In other aspects, the invention provides methods to treat conditionsassociated with excessive superoxide formation. SOD mimetics have beenshown to exhibit in vitro and in vivo activity in models forinflammation, myocardial ischemia-reperfusion injury, and vascularrelaxation and restenosis. D. P. Riley, et al., Adv. Supramol. Chem.,vol. 6, 217-244 (2000). Specific conditions for which SOD mimeticcompounds are reported to be useful include inflammatory diseases anddisorders, such as reperfusion injury to the ischemic myocardium,inflammatory bowel disease, rheumatoid arthritis, osteoarthritis,atherosclerosis, hypertension, metastasis, psoriasis, organ transplantrejections, radiation-induced injury, asthma, influenza, stroke, burnsand trauma, as well as for treatment of localized inflammation, edema,and pain. The compounds are also beneficial for treatment of certainaspects of neuronal apoptosis, cancer and acquired immunodeficiencysyndrome (AIDS).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts selected macrocycles reported to have activity as SODmimetics.

FIG. 2 depicts selected exemplary species within the current invention,showing only the neutral form of the molecule without a chelated metal.

MODES OF CARRYING OUT THE INVENTION

As used herein, “hydrocarbyl residue” refers to a residue which containsonly carbon and hydrogen. The residue may be aliphatic or aromatic,straight-chain, cyclic, branched, saturated or unsaturated, or anycombination of these. The hydrocarbyl residue, when so stated, however,may contain heteroatoms in addition to or instead of the carbon andhydrogen members of the hydrocarbyl group itself. Thus, whenspecifically noted as containing or optionally containing heteroatoms,the hydrocarbyl group may contain one or more heteroatoms as indicatedwithin the “backbone” of the hydrocarbyl residue, and when optionallysubstituted, the hydrocarbyl residue may also have one or more carbonylgroups, amino groups, hydroxyl groups and other suitable substituents asfurther described herein in place of one or more hydrogens of the parenthydrocarbyl residue.

As used herein, the terms “alkyl,” “alkenyl” and “alkynyl” includestraight-chain, branched-chain and cyclic monovalent hydrocarbylradicals, and combinations of these, which contain only C and H whenthey are unsubstituted. Examples include methyl, ethyl, isobutyl,cyclohexyl, cyclopentylethyl, 2-propenyl, 3-butynyl, and the like. Thetotal number of carbon atoms in each such group is sometimes describedherein, e.g., when the group can contain up to ten carbon atoms it maybe described as 1-10C or as C1-C10 or as C1-10. When heteroatoms(typically N, O and S) are allowed to replace carbon atoms of an alkyl,alkenyl or alkynyl group, as in heteroalkyl groups, for example, thenumbers describing the group, though still written as, e.g., C1-C6,represent the sum of the number of carbon atoms in the group plus thenumber of such heteroatoms that are included as replacements for carbonatoms in the ring or chain being described.

Typically, the alkyl, alkenyl and alkynyl substituents of the inventioncontain 1-10C (alkyl) or 2-10C (alkenyl or alkynyl). Preferably theycontain 1-8C (alkyl) or 2-8C (alkenyl or alkynyl). Sometimes theycontain 1-4C (alkyl) or 2-4C (alkenyl or alkynyl). A single group caninclude more than one type of multiple bond, or more than one multiplebond; such groups are included within the definition of the term“alkenyl” when they contain at least one carbon-carbon double bond, andthey are included within the term “alkynyl” when they contain at leastone carbon-carbon triple bond.

Alkyl, alkenyl and alkynyl groups are often substituted to the extentthat such substitution makes sense chemically. Typical substituentsinclude, but are not limited to, halo, ═O, ═N—CN, ═N—OR, ═NR, OR, NR₂,SR, SO₂R, SO₂NR₂, NRSO₂R, NRCONR₂, NRCOOR, NRCOR, CN, COOR, CONR₂, OOCR,COR, and NO₂, wherein each R is independently H, C1-C8 alkyl, C2-C8heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C2-C8 alkenyl, C2-C8heteroalkenyl, C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, orC5-C10 heteroaryl, and each R is optionally substituted with one or moregroups selected from halo, ═O, ═N—CN, ═N—OR′, ═NR′, OR′, NR′₂, SR′,SO₂R′, SO₂NR′₂, NR′SO₂R′, NR′CONR′₂, NR′COOR′, NR′COR′, CN, COOR′,CONR′₂, OOCR′, COR′, and NO₂, wherein each R′ is independently H, C1-C8alkyl, C2-C8 heteroalkyl, C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl orC5-C10 heteroaryl, and wherein two R or R′ on the same or adjacent atomscan optionally cyclize to form a ring. Alkyl, alkenyl and alkynyl groupscan also be substituted by C1-C8 acyl, C2-C8 heteroacyl, C6-C10 aryl orC5-C10 heteroaryl, each of which can be substituted by the substituentsthat are appropriate for the particular group.

“Heteroalkyl”, “heteroalkenyl”, and “heteroalkynyl” and the like aredefined similarly to the corresponding hydrocarbyl (alkyl, alkenyl andalkynyl) groups, but the ‘hetero’ terms refer to groups that contain oneor more heteroatoms selected from O, S and N and combinations thereof,within the backbone residue; thus at least one carbon atom of acorresponding alkyl, alkenyl, or alkynyl group is replaced by one of thespecified heteroatoms to form a heteroalkyl, heteroalkenyl, orheteroalkynyl group. Preferably, each heteroalkyl, heteroalkenyl andheteroalkynyl group contains only one heteroatom or 1-2 heteroatoms.Such ‘hetero’ groups are, however, still linked to the base molecule viaa carbon atom.

The typical and preferred sizes for heteroforms of alkyl, alkenyl andalkynyl groups are generally the same as for the correspondinghydrocarbyl groups, and the substituents that may be present on theheteroforms are the same as those described above for the hydrocarbylgroups. Where such groups contain N, the nitrogen atom may be present asNH or it may be substituted if the heteroalkyl or similar group isdescribed as optionally substituted. Where such groups contain S, thesulfur atom may optionally be oxidized to SO or SO₂ unless otherwiseindicated. For reasons of chemical stability, it is also understoodthat, unless otherwise specified, such groups do not include more thantwo contiguous heteroatoms except where an oxo group is present on N orS as in a nitro or sulfonyl group.

While “alkyl” as used herein includes cycloalkyl and cycloalkylalkylgroups, the term “cycloalkyl” may be used herein to specificallydescribe a carbocyclic non-aromatic group that is connected via a ringcarbon atom, and “cycloalkylalkyl” may be used to describe a carbocyclicnon-aromatic group that is connected to the base molecule through analkyl linker. Similarly, “heterocyclyl” may be used to describe anon-aromatic cyclic group that contains at least one heteroatom as aring member and that is connected to the molecule via a ring atom of thecyclic group, which may be C or N; and “heterocyclylalkyl” may be usedto describe such a group that is connected to another molecule throughan alkyl linker. The sizes and substituents that are suitable for thecycloalkyl, cycloalkylalkyl, heterocyclyl, and heterocyclylalkyl groupsare the same as those described above for alkyl groups. The size of acycloalkylalkyl or heterocyclylalkyl group describes the total number ofcarbon atoms or of carbon atoms plus heteroatoms that replace carbonatoms of an alkyl, alkenyl, alkynyl, cycloalkyl, or alkylenyl portion.As used herein, these terms also include rings that contain a doublebond or two, as long as the ring is not aromatic.

As used herein, “acyl” encompasses groups comprising an alkyl, alkenyl,alkynyl, aryl or arylalkyl radical attached at one of the two availablevalence positions of a carbonyl carbon atom, e.g., —C(═O)R where R is analkyl, alkenyl, alkynyl, aryl, or arylalkyl group, and heteroacyl refersto the corresponding groups wherein at least one carbon other than thecarbonyl carbon has been replaced by a heteroatom chosen from N, O andS. Thus heteroacyl includes, for example, —C(═O)OR and —C(═O)NR₂ as wellas —C(═O)-heteroaryl.

Acyl and heteroacyl groups are bonded to any group or molecule to whichthey are attached through the open valence of the carbonyl carbon atom.Typically, they are C1-C8 acyl groups, which include formyl, acetyl,pivaloyl, and benzoyl, and C2-C8 heteroacyl groups, which includemethoxyacetyl, ethoxycarbonyl, and 4-pyridinoyl. The hydrocarbyl groups,aryl groups, and heteroforms of such groups that comprise an acyl orheteroacyl group can be substituted with the substituents describedherein as generally suitable substituents for each of the correspondingcomponent of the acyl or heteroacyl group.

“Aromatic” moiety or “aryl” moiety refers to a monocyclic or fusedbicyclic moiety having the well-known characteristics of aromaticity;examples include phenyl and naphthyl. Similarly, “heteroaromatic” and“heteroaryl” refer to such monocyclic or fused bicyclic ring systemswhich contain as ring members one or more heteroatoms selected from O, Sand N. The inclusion of a heteroatom permits aromaticity in 5-memberedrings as well as 6-membered rings. Typical heteroaromatic systemsinclude monocyclic C5-C6 aromatic groups such as pyridyl, pyrimidyl,pyrazinyl, thienyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl,and imidazolyl, and the fused bicyclic moieties formed by fusing one ofthese monocyclic groups with a phenyl ring or with any of theheteroaromatic monocyclic groups to form a C8-C10 bicyclic group such asindolyl, benzimidazolyl, indazolyl, benzotriazolyl, isoquinolyl,quinolyl, benzothiazolyl, benzofuranyl, pyrazolopyridyl, quinazolinyl,quinoxalinyl, cinnolinyl, and the like. Any monocyclic or fused ringbicyclic system which has the characteristics of aromaticity in terms ofelectron distribution throughout the ring system is included in thisdefinition. It also includes bicyclic groups where at least the ringwhich is directly attached to the remainder of the molecule has thecharacteristics of aromaticity, even though it may be fused to anonaromatic ring. Typically, the ring systems contain 5-12 ring memberatoms. Preferably the monocyclic heteroaryl groups contain 5-6 ringmembers, and the bicyclic heteroaryls contain 8-10 ring members.

Aryl and heteroaryl moieties may be substituted with a variety ofsubstituents including C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C5-C12aryl, C1-C8 acyl, and heteroforms of these, each of which can itself befurther substituted; other substituents for aryl and heteroaryl moietiesinclude halo, OR, NR₂, SR, SO₂R, SO₂NR₂, NRSO₂R, NRCONR₂, NRCOOR, NRCOR,CN, COOR, CONR₂, OOCR, —C(O)R, and NO₂, wherein each R is independentlyH, C1-C8 alkyl, C2-C8 heteroalkyl, C2-C8 alkenyl, C2-C8 heteroalkenyl,C2-C8 alkynyl, C2-C8 heteroalkynyl, C6-C10 aryl, C5-C10 heteroaryl,C7-C12 arylalkyl, or C6-C12 heteroarylalkyl, and each R is optionallysubstituted as described above for alkyl groups. The substituent groupson an aryl or heteroaryl group may of course be further substituted withthe groups described herein as suitable for each type of group thatcomprises the substituent. Thus, for example, an arylalkyl substituentmay be substituted on the aryl portion with substituents describedherein as typical for aryl groups, and it may be further substituted onthe alkyl portion with substituents described herein as typical orsuitable for alkyl groups.

Similarly, “arylalkyl” and “heteroarylalkyl” refer to aromatic andheteroaromatic ring systems which are bonded to their attachment pointthrough a linking group such as an alkylene, including substituted orunsubstituted, saturated or unsaturated, cyclic or acyclic linkers.Typically the linker is C1-C8 alkyl or a hetero form thereof. Theselinkers may also include a carbonyl group, thus making them able toprovide substituents as an acyl or heteroacyl moiety.

An aryl or heteroaryl ring in an arylalkyl or heteroarylalkyl group maybe substituted with the same substituents described above for arylgroups. Preferably, an arylalkyl group includes a phenyl ring optionallysubstituted with the groups defined above for aryl groups and a C1-C4alkylene that is unsubstituted or is substituted with one or two C1-C4alkyl groups or heteroalkyl groups, where the alkyl or heteroalkylgroups can optionally cyclize to form a ring such as cyclopropane,dioxolane, or oxacyclopentane.

Similarly, a heteroarylalkyl group preferably includes a C5-C6monocyclic heteroaryl group that is optionally substituted with thegroups described above as substituents typical on aryl groups and aC1-C4 alkylene that is unsubstituted or is substituted with one or twoC1-C4 alkyl groups or heteroalkyl groups, or it includes an optionallysubstituted phenyl ring or C5-C6 monocyclic heteroaryl and a C1-C4heteroalkylene that is unsubstituted or is substituted with one or twoC1-C4 alkyl or heteroalkyl groups, where the alkyl or heteroalkyl groupscan optionally cyclize to form a ring such as cyclopropane, dioxolane,or oxacyclopentane.

Where an arylalkyl or heteroarylalkyl group is described as optionallysubstituted, the substituents may be on either the alkyl or heteroalkylportion or on the aryl or heteroaryl portion of the group. Thesubstituents optionally present on the alkyl or heteroalkyl portion arethe same as those described above for alkyl groups generally; thesubstituents optionally present on the aryl or heteroaryl portion arethe same as those described above for aryl groups generally.

“Arylalkyl” groups as used herein are hydrocarbyl groups if they areunsubstituted, and are described by the total number of carbon atoms inthe ring and alkylene or similar linker. Thus a benzyl group is aC7-arylalkyl group, and phenylethyl is a C8-arylalkyl.

“Heteroarylalkyl” as described above refers to a moiety comprising anaryl group that is attached through a linking group, and differs from“arylalkyl” in that at least one ring atom of the aryl moiety or oneatom in the linking group is a heteroatom selected from N, O and S. Theheteroarylalkyl groups are described herein according to the totalnumber of atoms in the ring and linker combined, and they include arylgroups linked through a heteroalkyl linker; heteroaryl groups linkedthrough a hydrocarbyl linker such as an alkylene; and heteroaryl groupslinked through a heteroalkyl linker. Thus, for example,C7-heteroarylalkyl would include pyridylmethyl, phenoxy, andN-pyrrolylmethoxy.

“Alkylene” as used herein refers to a divalent hydrocarbyl group;because it is divalent, it can link two other groups together. Typicallyit refers to —(CH₂)_(n)— where n is 1-8 and preferably n is 1-4, thoughwhere specified, an alkylene can also be substituted by other groups,and can be of other lengths, and the open valences need not be atopposite ends of a chain. Thus —CH(Me)— and —C(Me)₂- may also bereferred to as alkylenes, as can a cyclic group such ascyclopropan-1,1-diyl. Where an alkylene group is substituted, thesubstituents include those typically present on alkyl groups asdescribed herein.

In general, any alkyl, alkenyl, alkynyl, acyl, or aryl or arylalkylgroup or any heteroform of one of these groups that is contained in asubstituent may itself be optionally substituted by additionalsubstituents. The nature of these substituents is similar to thoserecited with regard to the primary substituents themselves if thesubstituents are not otherwise described. Thus, where an embodiment of,for example, R⁷ is alkyl, this alkyl may optionally be substituted bythe remaining substituents listed as embodiments for R⁷ where this makeschemical sense, and where this does not undermine the size limitprovided for the alkyl per se; e.g., alkyl substituted by alkyl or byalkenyl would simply extend the upper limit of carbon atoms for theseembodiments, and is not intended to be included. However, alkylsubstituted by aryl, amino, alkoxy, ═O, and the like would be includedwithin the scope of the invention, and the atoms of these substituentgroups are not counted in the number used to describe the alkyl,alkenyl, etc. group that is being described. Where no number ofsubstituents is specified, each such alkyl, alkenyl, alkynyl, acyl, oraryl group may be substituted with a number of substituents according toits available valences and in accord with known principles of chemicalstability; in particular, any of these groups may be substituted withfluorine atoms at any or all of the available valences on carbon atoms,for example.

“Heteroform” as used herein refers to a derivative of a group such as analkyl, aryl, or acyl, wherein at least one carbon atom of the designatedcarbocyclic group has been replaced by a heteroatom selected from N, Oand S. Thus the heteroforms of alkyl, alkenyl, alkynyl, acyl, aryl, andarylalkyl are heteroalkyl, heteroalkenyl, heteroalkynyl, heteroacyl,heteroaryl, and heteroarylalkyl, respectively. It is understood that nomore than two N, O or S atoms are ordinarily connected sequentially,except where an oxo group is attached to N or S to form a nitro orsulfonyl group.

“Optionally substituted” as used herein indicates that the particulargroup or groups being described may have no non-hydrogen substituents,or the group or groups may have one or more non-hydrogen substituents.If not otherwise specified, the total number of such substituents thatmay be present is equal to the number of H atoms present on theunsubstituted form of the group being described. Where an optionalsubstituent is attached via a double bond, such as a carbonyl oxygen(═O), the group takes up two available valences, so the total number ofsubstituents that may be included is reduced according to the number ofavailable valences.

“Halo”, as used herein includes fluoro, chloro, bromo and iodo. Fluoroand chloro are often preferred.

“Amino” as used herein refers to NH₂, but where an amino is described as“substituted” or “optionally substituted”, the term includes NR′R″wherein each R′ and R″ is independently H, or is an alkyl, alkenyl,alkynyl, acyl, aryl, or arylalkyl group or a heteroform of one of thesegroups, and each of the alkyl, alkenyl, alkynyl, acyl, aryl, orarylalkyl groups or heteroforms of one of these groups is optionallysubstituted with the substituents described herein as suitable for thecorresponding type of group. The term also includes forms wherein R′ andR″ are linked together to form a 3-8 membered ring which may besaturated, unsaturated or aromatic and which contains 1-3 heteroatomsindependently selected from N, O and S as ring members, and which isoptionally substituted with the substituents described as suitable foralkyl groups or, if NR′R″ is an aromatic group, it is optionallysubstituted with the substituents described as typical for heteroarylgroups.

As used herein, an ‘azaycyclic’ group refers to a heterocyclic groupcontaining at least one nitrogen as a ring atom, wherein the group isattached to the base molecule through a nitrogen atom of the azacyclicring. Typically these azacyclic groups are 3-8 membered monocyclic ringsor 8-12 membered bicyclic fused ring systems. An azacyclic group havingmore than four ring members can optionally include one additionalheteroatom selected from N, O and S, and an azacyclic group having morethan six ring members can optionally include one or two additionalheteroatoms selected from N, O and S. Typically, an azacyclic group isnon-aromatic, and such azacyclic groups can optionally be substitutedwith substituents that are suitable for alkyl groups. Typical examplesof azacyclic groups include pyrrolidine, pyrrolidinone, piperidine,morpholine, thiomorpholine, and piperazine. In certain embodiments, anazacyclic group can be aromatic, provided that at least one ringnitrogen atom is in a five membered ring so the nitrogen can serve asthe point of attachment to the base molecule. Examples of aromaticsystems that can be azacyclic groups include pyrrole, imidazole,pyrazole, or indole.

The compounds of formulas (1)-(3) are 16-membered macrocyclic rings, andmay be complexed to a metal M, or they may be metal-free, in which caseM represents H. In preferred embodiments, M is H, Fe or Mn. Forpharmaceutical compositions, typically M represents Mn or Fe, usually ina plus three oxidation state. In specific embodiments, M representsMn(III). However, it is understood in the art that the superoxidedismutation process typically involves a metal center cycling betweentwo different oxidation states, such as Fe(II)/Fe(III) orMn(II)/Mn(III). Accordingly, the invention encompasses complexes whereinthe metal cation is in any of these oxidation states.

Each R¹ in formulas (1)-(3) represents an optional substituent on atetravalent carbon; valences of such carbons not occupied by a specifiedsubstituent such as R¹ are occupied by H as is understood in the art. Inmany embodiments, each R¹ present is an alkyl group such as methyl. Inother embodiments two R¹ groups on adjacent carbons are linked to form afive or six membered saturated hydrocarbon ring (cyclopentane orcyclohexane) that is fused to the 16-membered macrocyclic ring, and suchfused rings may be substituted. Such fused rings substantially influencethe conformation of the macrocyclic ring, and may be positioned toenhance the SOD mimetic activity by favoring a conformation for themacrocycle that is conducive to complexation to a particular metalcation. In a preferred embodiment, at least one such ring is fused ontothe macrocycle at positions 6 and 7 of the macrocycle, or at positions15 and 16 of the macrocycle; in other embodiments, two such rings arefused onto the macrocycle, with one fused at positions 6 and 7, and theother fused at positions 15 and 16. These fused rings can be fused tothe macrocycle with either a cis ring fusion or a trans ring fusion, asis understood in the art; and in preferred embodiments, a fused ring ofthis type is fused to the macrocycle with a trans ring fusion. Where twosuch fused rings are present, as when one such ring is fused onto themacrocycle at positions 6 and 7 of the macrocycle, or at positions 15and 16 of the macrocycle, each such ring is preferably fused to themacrocycle in a trans fusion.

Each R² in formulas (1)-(3) independently represents an optionalsubstituent on a trivalent carbon; valences of such carbons not occupiedby a specified substituent are also occupied by H. Two R² groups onadjacent carbons can optionally be linked to form a fused ring,including a fused aromatic or heteroaromatic ring having five, orpreferably six, ring members. In certain embodiments, R² at position 2of the macrocycle represents methyl, or R² at position 4 of themacrocycle represents methyl, and in some embodiments R² at bothpositions 2 and 4 represent methyl.

Each n and each p in formulas (1)-(3) can independently be 0, 1 or 2;where n or p is 0, the corresponding carbon atom of the macrocyclic ringis unsubstituted, which means it has two hydrogens as is understood inthe art. Where n or p is 1, the corresponding carbon atom of themacrocycle has one substituent and one hydrogen atom. Where n or p is 2,there are two R¹ groups on a single carbon of the macrocycle, and thosetwo R¹ groups may cyclize to form a ring such as a cyclopropane having3-8 ring atoms and optionally containing a heteroatom selected from N, Oand S, and optionally substituted with the typical substituents that maybe present on alkyl groups. In certain embodiments, each p is 0. Inother embodiments p is 1 at two adjacent carbons of the macrocycle, andthe corresponding R¹ groups may cyclize as further described below. Incertain embodiments, n is 1 at one or more of positions 6, 7, 15 and 16of the macrocycle. In some such embodiments, n is 1 at each of thesepositions, or at two adjacent positions. In such embodiments, two R¹groups ma be on adjacent carbons of the macrocycle, and may cyclize asfurther described below. The compounds of formula (3) represent aparticular embodiment where substituent groups represented as R^(1a)groups are present on specified positions, and in formula (3) therelative stereochemistry of the R^(1a) groups is also specified andcorresponds to an orientation that provides particularly good SODmimetic activity due apparently to preferentially maintaining anespecially suitable conformation for the macrocycle to coordinate to M.Formula (3) illustrates a specific enantiomeric configuration, however,and the enantiomeric form of the SOD mimetics is not necessarilycritical to their function. Accordingly, compounds that have the samerelative configuration depicted in formula (3) but the opposite absolutestereochemistry, are expected to be similarly effective as SOD mimeticsand are included in the invention. Thus formula (3) is understood toconvey a preferred relative orientation for substituents R^(1a) on themacrocycle but includes both enantiomeric forms of the macrocycle.

Similarly, where two R¹ or two R² groups are present on adjacent carbonatoms of the macrocycle, those two R¹ groups or two R² groups maycyclize to form a ring such as a cyclopropane, cyclopentane orcyclohexane having 3-8 ring atoms and optionally containing a heteroatomselected from N, O and S, and optionally substituted with the typicalsubstituents that may be present on alkyl groups.

Each m in formulas (1)-(3) is independently 0 or 1; where m is 0, thecorresponding carbon of the macrocycle has a hydrogen atom and noadditional substituent. In certain embodiments, however, each m is zero,so no R² groups are present on the macrocycle.

Each R³ in formulas (1)-(3) independently represents H or a protectinggroup that can readily be lost in vivo. As is understood, when M is ametal, it will be coordinated to each nitrogen having an R³ group eventhough that relationship is not depicted expressly in the structures asdrawn. In many embodiments, each R³ represents H. However, if one ormore R³ represents a protecting group that can be cleaved under normalphysiological conditions, the compound will still exhibit the desiredphysiological activity. Certain acyl groups, particularly trifluoracetyland other perfluoracyl groups, are examples of such protecting groupsthat dissociate from nitrogen in vivo and can provide biologicallyactive SOD mimetics when administered. Accordingly, compounds wherein atleast one R³ group represents such a protecting group are included inthe invention.

Compounds wherein one or more of the R³ groups represents a protectinggroup that does not hydrolyze off under physiological conditions may notexhibit SOD mimetic activity in vivo. However, they are useful asprecursors to the compounds wherein each R³ is H, for example, and arethus still part of the invention. The use and particularly the removalof such protecting groups are well known in the art. Examples ofsuitable protecting groups for R³ include, but are not limited to,formyl, acetyl, C1-C4 alkoxycarbonyl, trichloroacetyl, benzoyl,benzyloxycarbonyl, benzyl, and the like. Examples of such protectinggroups and methods for the attachment and removal of such protectinggroups are extensively documented in, for example, T. W. Greene's bookentitled Protective Groups in Organic Synthesis, Wiley Intersciences,2^(nd) ed. (1991), which is incorporated herein by reference.

Typically, the SOD mimetic compounds of the invention are used ascomplexes wherein M represents a cationic metal species. The macrocycliccompounds, wherein M represents H, may be useful as prodrugs, becausetheir affinity for chelating suitable metals in vivo is high: they canform active complexes with available metals such as Fe³⁺ in the body.The non-complexed macrocycles are also useful as precursors to complexeswherein M represents a metal such as Mn⁺³ or Fe⁺³.

L in formulas (1) and (3) represents a three atom linker connecting thecarbon atoms at positions 9 and 13 of the macrocycle. In someembodiments, L is C(R₁)_(p)—NR³—C(R¹)_(p) wherein R¹, p and R³ are asdescribed above. These correspond, for example, to compounds of formula(2a). In other embodiments, L represents a pyridyl ring that is attachedto the macrocycle by the pyridyl carbons at positions 2 and 6, where thepyridyl ring is position 1 as it is conventionally considered to be.These correspond, for example, to compounds of general formula (2b). Thepyridyl nitrogen then serves as one of the coordinating atoms for M if Mrepresents a metal ion. Such pyridyl ring may be further substitutedwith substituent groups that are typically present on aromatic orheteroaromatic rings. In many embodiments, this pyridyl ring is notfurther substituted. In other embodiments it has one substituent that isat the 4-position on the pyridyl ring, and is preferably an optionallysubstituted C1-C4 alkyl or C5-C6 aryl group, or a heteroform of one ofthese groups. In certain embodiments, the pyridyl ring has one or twosubstituents. Preferred substituents if any are present, include phenyl,methyl, halo, especially chloro or fluoro, trifluoromethyl,trifluoromethoxy, and methoxy.

The compounds of the invention may and often do contain chiral centers,which may be included in the macrocycle or elsewhere. The inventionexpressly includes each enantiomer as well as each diastereomer of thecompounds described and mixtures thereof, particularly racemic mixturesand highly enriched enantiomers having an enantiomeric excess (ee) ofgreater than 90% or greater than about 95%. Substituent groups may alsoinclude one or more chiral centers, and each enantiomer and diastereomeras well as mixtures thereof are all included within the scope of theinvention. Similarly, where double bonds are present, the compounds canexist in some cases as cis or trans isomers; the invention includes eachisomer.

Merely as examples of selected compounds of the invention, FIG. 2illustrates a number of compounds of formula (1). These representselected preferred species, and other species that include combinationsof the features in the compounds specifically depicted are alsopreferred.

The compounds of the invention may be isolated as salts where anionizable group such as a basic amine or a carboxylic acid is present.The invention includes the salts of these compounds, which are useful asintermediates and as precursors to the complexes of formulas (1)-(3).The complexes themselves may be considered salts in some instances, andmay exist in various protonated forms depending on the nature of M andthe pH of the environment. In particular, the pharmaceuticallyacceptable salts of the compounds of formulas (1)-(3) are included,because they are useful in the claimed methods and pharmaceuticalcompositions. Such salts are well known in the art, and include, forexample, salts of acidic groups formed by reaction with organic orinorganic bases, and salts of basic groups formed by reaction withorganic or inorganic acids, as long as the counterions introduced by thereaction are acceptable for pharmaceutical uses. Examples of inorganicbases with alkali metal hydroxides (e.g., sodium hydroxide, potassiumhydroxide, etc.), alkaline earth metal hydroxides (e.g., of calcium,magnesium, etc.), and hydroxides of aluminum, ammonium, etc.

Examples of organic bases that could be used include trimethylamine,triethylamine, pyridine, picoline, ethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, N,N′-dibenzylethylenediamine, etc.Examples of inorganic acids that could be used include hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid,etc. Examples of organic acids include formic acid, oxalic acid, aceticacid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, malicacid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonicacid, etc. Also included are salts with basic amino acids such asarginine, lysine, ornithine, etc., and salts with acidic amino acidssuch as aspartic acid, glutamic acid, etc.

Compounds of the invention may be prepared using methods generally knownin the art. In particular, the compounds of the invention are oftenprepared from a compound of formula (5) by reaction with a1,3-dicarbonyl compound as illustrated in Scheme I. Suitable1,3-dicarbonyl compounds of formula (6) are well known in the art.

Reactions of this general type are well known to proceed to producecertain ring structures; however, in preparing the macrocyclic compoundsof the invention, conventional conditions are not very efficient due topolymerization and side reactions. Accordingly, the reaction depicted inScheme I is typically performed in the presence of a multivalent metalcation that acts as a template to favor formation of the desiredmacrocycles and in the presence of an equivalent of base to accept aproton from the 1,3-dicarbonyl compound (6).

[M] represents a metal cation that is used to facilitate formation ofthe desired macrocycle.

Compounds similar to the intermediate of formula (5) and methods fortheir preparation are also known in the art; for example, applicablemethods for their synthesis are described in D. P. Riley, et al., J.Inorg. Chem. vol. 35, 5213-31 (1996). Applicable methods are alsodescribed in U.S. Pat. No. 5,637,578 to Riley, et al., which is alsoincorporated herein by reference. Many of the synthesis methods in thesereferences disclose synthesis of precursors having only three of thenitrogen atoms required for the macrocycles of the invention. Wherethese references describe preparation of such intermediates, the methodscan be applied using conventional methods to introduce two additionalnitrogen atoms in a protected form. For example, preparations ofintermediates of formula (7) are reported, and these compounds can beconverted into compounds of formula (5) as shown in Scheme 2. In formula(8) of Scheme 2, X represents a protecting functionality, and each R³ isa protecting group suitable for reaction conditions that the moleculewill be exposed to. The other groups are as defined for formula (1).

The reaction sequence in Scheme 2 requires the nitrogen atoms in formula(7) to be protected. The protecting groups used can be those used in thereferences, for example toluenesulfonate (Ts) can be used. However, awide variety of alternative protecting groups such as benzyl, CBZ, tBOC,and various other acyl groups such as trichloroacetyl can also be used,and require only variations of conditions that are known to those ofordinary skill. Scheme 2 as shown indicates that a tosylate leavinggroup (OTs) can be employed; as those of skill in the art recognize,other leaving groups suitable for nucleophilic replacement can also beused.

The “N-synthon” in Scheme 2 refers to a nucleophilic species that reactswith an alkylating agent such as compounds of formula (7) to place anitrogen atom directly on the carbon where displacement occurs. Avariety of suitable N-synthons are well known in the art; illustrativeexamples include azide (N₃ ⁻) and phthalimide anion. These are efficientreagents that can be used to introduce the N—X groups depicted informula (8), where X indicates that the nitrogen atom is in a protectedform. If azide is used as the N-synthon, it can be reduced to form theamine of formula (5) using standard conditions such as, for example,catalytic hydrogenation. Likewise, if phthalimide anion (e.g., sodiumphthalimide) is used, the phthalimide group can be removed usinghydrazine or other conventional means. As those skilled in the art willappreciate, the selection of the N-synthon and the protecting group R³can be varied to accommodate a wide variety of substituents on themacrocycle precursors and to permit removal of X and/or R³ at anappropriate time.

It is typically desirable to remove each R³ and X in order to cyclize acompound of formula (8) or (5) using a metal cation as the cyclizationtemplate. In some embodiments, one or more R³ groups may not be H whenthe cyclization is effected. The cyclization is best accomplished in thepresence of a metal cation that provides a template to hold the acyclicpolyaza compound of formula (5) in a suitable conformation to facilitatemacrocycle formation. Suitable metal cations for this include, but arenot limited to, Fe(II), Fe(III), Mn(II), Mn(III), and other transitionmetal cations having a plus two or plus three oxidation state.

The compounds of the invention can be used to prepare pharmaceuticalcompositions containing at least one compound of any of formulas(1)-(3). Such compositions can be optimized for various conditions androutes of administration using guidance that is widely relied on forsuch purposes including Remington's Pharmaceutical Sciences, latestedition, Mack Publishing Co., Easton, Pa., which is incorporated hereinby reference. The compositions comprise a compound of the inventionadmixed with at least one pharmaceutically acceptable excipient, andpreferably with at least one such excipient other than water or asolvent such as DMSO.

Formulations may be prepared in a manner suitable for systemicadministration or topical or local administration. Systemic formulationsinclude those designed for injection (e.g., intramuscular, intravenousor subcutaneous injection) or may be prepared for transdermal,transmucosal, or oral administration. The formulation will generallyinclude a diluent as well as, in some cases, adjuvants, buffers,preservatives and the like. The compounds can be administered also inliposomal compositions or as microemulsions.

Injection methods are sometimes appropriate routes for administration ofthe compounds for systemic treatments and sometimes also for localizedtreatments. These include methods for intravenous, intramuscular,subcutaneous, and other methods for internal delivery that bypass themucosal and dermal barriers to deliver the composition directly into thesubject's living tissues.

For injection, formulations can be prepared in conventional forms asliquid solutions or suspensions or as solid forms suitable for solutionor suspension in liquid prior to injection or as emulsions. Suitableexcipients include, for example, water, saline, dextrose, glycerol andthe like. Such compositions may also contain amounts of nontoxicauxiliary substances such as wetting or emulsifying agents, pH bufferingagents and the like, such as, for example, sodium acetate, sorbitanmonolaurate, and so forth.

Various sustained release systems for drugs have also been devised. See,for example, U.S. Pat. No. 5,624,677. The present compositions can beutilized in such controlled-release delivery systems where appropriate.

Systemic administration may also include relatively noninvasive methodssuch as the use of suppositories, transdermal patches, transmucosaldelivery and intranasal administration. Oral administration is alsosuitable for compounds of the invention. Suitable forms include syrups,capsules, tablets, and the like as in understood in the art. Selectionof a particular route for a given subject is well within the ordinarylevel of skill in the art. For example, rectal delivery as a suppositoryis often appropriate where the subject experiences nausea and vomitingthat precludes effective oral delivery. Transdermal patches are commonlycapable of delivering a controlled-release dosage over several days orto a specific locus, and are thus suitable for subjects where theseeffects are desired.

Transmucosal delivery is also appropriate for some of the compositionsand methods of the invention. Thus the compositions of the invention maybe administered transmucosally using technology and formulation methodsthat are known in the art.

For administration to animal or human subjects, the dosage of a compoundof the invention is typically 10-2400 mg per administration. However,dosage levels are highly dependent on the nature of the condition, thecondition of the patient, the judgment of the practitioner, and thefrequency and mode of administration. Selection of a dosage of suchcompounds is within the skill of an ordinary artisan, and may beaccomplished by starting at a relatively low dosage and increasing thedosage until an acceptable effect is achieved.

Example 1

The following enumerated embodiments are presented it illustrate certainaspects of the present invention, and are not intended to limit itsscope.

1. A compound of formula (1):

wherein:

each R¹ is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl,or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl),each of which can be substituted with one or more groups selected fromhalo, ═O, OR, S(O)_(t)R, NR₂, COOR, CONR₂, wherein t can be 0-2 and eachR independently represents H, C1-C4 alkyl, and wherein two R groups onone N can cyclize to form a saturated azacyclic group;

each R² is independently C1-C10 alkyl, C6-C10 aryl, C5-C10 heteroaryl,or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10 heteroaryl)-(C1-C4 alkyl),each of which can be substituted with one or more groups selected fromhalo, OR, S(O)_(t)R, NR₂, COOR, CONR₂, wherein t can be 0-2 and each Rindependently represents H, C1-C4 alkyl, and wherein two R groups on oneN can cyclize to form a saturated azacyclic group;

each R³ is H or a protecting group;

wherein any two R¹ on a single carbon can cyclize to form a ring having3-8 ring atoms, which ring can be substituted, and which can contain aheteroatom selected from N, O and S as a ring member;

and any two R¹ on adjacent carbon atoms, and any two R² groups onadjacent carbon atoms, can cyclize to form a ring having 3-8 ring atoms,which ring can be substituted and can be aromatic or non-aromatic, andcan contain a heteroatom selected from N, O and S as a ring member;

and any two of R¹ and R² on carbon atoms separated by a single Nitrogenatom can cyclize to form a ring having 3-8 atoms, which ring can besubstituted and can be aromatic or non-aromatic, and can contain, inaddition to the N between the carbon atoms to which linked groups areattached, an additional heteroatom selected from N, O and S as a ringmember;

each m is independently 0 or 1;

each n and p is independently 0-2;

L represents a three-atom linker that may be —C(R¹)_(p)—NR³—C(R¹)_(p)—or an optionally substituted pyridine-2,6-diyl group; and

M represents H or a metal cation;

or a pharmaceutically acceptable salt thereof.

2. The compound of embodiment 1, wherein M is a metal cation.

3. The compound of embodiment 2, wherein the metal cation is Mn (III) orMn(II).

4. The compound of any of embodiments 1-3, wherein each p is 0.

5. The compound of any of embodiments 1-4, wherein n is 1 for position 6and position 7, or wherein n is 1 for position 15 and position 16.

6. The compound of embodiment 5, wherein n is 1 for positions 6 and 7,and wherein R¹ groups at positions 6 and 7 cyclize to form a 5-8membered optionally substituted ring.

7. The compound of embodiment 6, wherein n is 1 for positions 15 and 16,and wherein R¹ groups at positions 15 and 16 cyclize to form a 5-8membered optionally substituted ring.

8. The compound of embodiment 7, wherein M represents Mn(III).

9. The compound of any of embodiments 1-8, wherein two R¹ groups onadjacent carbon atoms are in a trans orientation relative to each otheron the 16-membered ring of formula (1).

10. The compound of embodiment 9, wherein two R¹ groups at positions 6and 7 are in a trans orientation relative to each other on the16-membered ring of formula (1), and wherein two R¹ groups at positions15 and 16 are also in a trans orientation relative to each other on the16-membered ring of formula (1).

11. The compound of embodiment 10, wherein two R¹ groups at positions 6and 7 cyclize to form a cyclohexane or cyclopentane ring.

12. The compound of embodiment 11, wherein two R¹ groups at positions 15and 16 cyclize to form a cyclohexane or cyclopentane ring.

13. The compound of embodiment 3, wherein each n is 1, and each p is 0.

14. A compound of formula (2a):

wherein R¹, R², m, n, p and M are as defined for formula (1).

15. A compound of formula (2b):

wherein R¹, R², m, n, p and M are as defined for formula (1), and R⁴represents one or two optional substituents which may be present at anyposition(s) on the pyridine ring.

16. The compound of embodiment 14 or embodiment 15, wherein each p is 0.

17. The compound of embodiment 16, wherein two R¹ groups are in a transorientation relative to each other on the 16-membered ring of formula(1), and wherein said two R¹ groups cyclize to form a five or sixmembered ring.

18. The compound of embodiment 17, wherein M is Mn(III).

19. A compound of formula (3):

wherein R¹, R², R³, L, m, p and M are as defined above for formula (1),and wherein R^(1a) is an optionally substituted alkyl group, and whereintwo R^(1a) groups on adjacent carbons can link to form a ring.

20. The compound of any of embodiments 1-19, wherein M is H.

21. The compound of any of embodiments 1-20, wherein each R³ is H.

22. A method to treat conditions associated with excessive superoxideactivity, which method comprises administering to a patient in need ofsuch treatment the compound of any of embodiments 1-21.

23. A pharmaceutical composition comprising a compound according to anyof embodiments 1-21, admixed with at least one pharmaceuticallyacceptable excipient.

24. A method to promote decomposition of superoxide, which comprisesadding a compound of any of embodiments 1-21 to a medium containingsuperoxide or to a medium in which superoxide may be produced.

The foregoing examples are illustrative only, and do not represent anylimitation on the scope of the invention. Various modifications andcombinations of the features disclosed are apparent to those of skillbased on the above disclosure, and those are also within the scope ofthe invention.

The invention claimed is:
 1. A method to treat a condition associatedwith excessive superoxide activity wherein the condition is selectedfrom the group consisting of edema, vascular relaxation, osteoarthritis,rheumatoid arthritis, atherosclerosis, and inflammatory bowel disease,the method comprising administering to a patient in need of suchtreatment the compound of formula (1):

wherein: each R¹ is independently C1-C10 alkyl, C6-C10 aryl, C5-C10heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, ═O, OR, S(O)_(t)R, NR₂, COOR, CONR₂,wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl,and wherein two R groups on one N can cyclize to form a saturatedazacyclic group; each R² is independently C1-C10 alkyl, C6-C10 aryl,C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, OR, S(O)_(t)R, NR₂, COOR, CONR₂, whereint can be 0-2 and each R independently represents H, C1-C4 alkyl, andwherein two R groups on one N can cyclize to form a saturated azacyclicgroup; each R³ is H or a protecting group; wherein any two R¹ on asingle carbon can cyclize to form a ring having 3-8 ring atoms, whichring can be substituted, and which can contain a heteroatom selectedfrom N, O and S as a ring member; and any two R¹ on adjacent carbonatoms, and any two R² groups on adjacent carbon atoms, can cyclize toform a ring having 3-8 ring atoms, which ring can be substituted and canbe aromatic or non-aromatic, and can contain a heteroatom selected fromN, O and S as a ring member; and any two of R¹ and R² on carbon atomsseparated by a single Nitrogen atom can cyclize to form a ring having3-8 atoms, which ring can be substituted and can be aromatic ornon-aromatic, and can contain, in addition to the N between the carbonatoms to which linked groups are attached, an additional heteroatomselected from N, O and S as a ring member; each m is independently 0 or1; each n and p is independently 0-2; L represents a three-atom linkercorresponding to —C(R¹)_(p)—NR³—C(R¹)_(p)— or an optionally substitutedpyridine-2,6-diyl group; and M represents H or a metal cation; or apharmaceutically acceptable salt thereof.
 2. The method of claim 1,wherein M is a metal cation.
 3. The method of claim 2, wherein the metalcation is Mn (III) or Mn(II).
 4. The method of claim 1, wherein each pis
 0. 5. The method of claim 1, wherein n is 1 for position 6 andposition 7, or wherein n is 1 for position 15 and position
 16. 6. Themethod of claim 5, wherein n is 1 for positions 6 and 7, and wherein R¹groups at positions 6 and 7 cyclize to form a 5-8 membered optionallysubstituted ring.
 7. The method of claim 6, wherein n is 1 for positions15 and 16, and wherein R¹ groups at positions 15 and 16 cyclize to forma 5-8 membered optionally substituted ring.
 8. The method of claim 6,wherein M represents Mn(III).
 9. The method of claim 1, wherein two R¹groups on adjacent carbon atoms are in a trans orientation relative toeach other on the 16-membered ring of formula (1).
 10. The method ofclaim 9, wherein two R¹ groups at positions 6 and 7 are in a transorientation relative to each other on the 16-membered ring of formula(1), and wherein two R¹ groups at positions 15 and 16 are also in atrans orientation relative to each other on the 16-membered ring offormula (1).
 11. The method of claim 10, wherein two R¹ groups atpositions 6 and 7 cyclize to form a cyclohexane or cyclopentane ring.12. The method of claim 11, wherein two R¹ groups at positions 15 and 16cyclize to form a cyclohexane or cyclopentane ring.
 13. The method ofclaim 2, wherein each n is 1, and each p is
 0. 14. The method of claim1, wherein the compound of formula (1) has the structure of formulae(2a) or (2b):

wherein: each R¹ is independently C1-C10 alkyl, C6-C10 aryl, C5-C10heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, ═O, OR, S(O)_(t)R, NR₂, COOR, CONR₂,wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl,and wherein two R groups on one N can cyclize to form a saturatedazacyclic group; each R² is independently C1-C10 alkyl, C6-C10 aryl,C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, OR, S(O)_(t)R, NR₂, COOR, CONR₂, whereint can be 0-2 and each R independently represents H, C1-C4 alkyl, andwherein two R groups on one N can cyclize to form a saturated azacyclicgroup; R⁴ represents one or two optional substituents which may bepresent at any position(s) on the pyridine ring wherein any two R¹ on asingle carbon can cyclize to form a ring having 3-8 ring atoms, whichring can be substituted, and which can contain a heteroatom selectedfrom N, O and S as a ring member; and any two R¹ on adjacent carbonatoms, and any two R² groups on adjacent carbon atoms, can cyclize toform a ring having 3-8 ring atoms, which ring can be substituted and canbe aromatic or non-aromatic, and can contain a heteroatom selected fromN, O and S as a ring member; and any two of R¹ and R² on carbon atomsseparated by a single Nitrogen atom can cyclize to form a ring having3-8 atoms, which ring can be substituted and can be aromatic ornon-aromatic, and can contain, in addition to the N between the carbonatoms to which linked groups are attached, an additional heteroatomselected from N, O and S as a ring member; each m is independently 0 or1; each n and p is independently 0-2; and M represents H or a metalcation; or a pharmaceutically acceptable salt thereof.
 15. The method ofclaim 14, wherein each p is
 0. 16. The method of claim 15, wherein twoR¹ groups are in a trans orientation relative to each other on the16-membered ring of formula (1), and wherein said two R¹ groups cyclizeto form a five or six membered ring.
 17. The method of claim 16, whereinM is Mn(III).
 18. The method of claim 1, wherein the compound of formula(1) has the structure of formula (3):

wherein: each R¹ is independently C1-C10 alkyl, C6-C10 aryl, C5-C10heteroaryl, or (C6-C10 aryl)-(C1-C4 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, ═O, OR, S(O)_(t)R, NR₂, COOR, CONR₂,wherein t can be 0-2 and each R independently represents H, C1-C4 alkyl,and wherein two R groups on one N can cyclize to form a saturatedazacyclic group; each R² is independently C1-C10 alkyl, C6-C10 aryl,C5-C10 heteroaryl, or (C6-C10 aryl)-(C1-04 alkyl), or (C5-C10heteroaryl)-(C1-C4 alkyl), each of which can be substituted with one ormore groups selected from halo, OR, S(O)_(t)R, NR₂, COOR, CONR₂, whereint can be 0-2 and each R independently represents H, C1-C4 alkyl, andwherein two R groups on one N can cyclize to form a saturated azacyclicgroup; each R³ is H or a protecting group; each R^(1a) is an optionallysubstituted alkyl group and wherein two R^(1a) groups on adjacent carbonatoms can link to form a ring; wherein any two R¹ on a single carbon cancyclize to form a ring having 3-8 ring atoms, which ring can besubstituted, and which can contain a heteroatom selected from N, O and Sas a ring member; and any two R¹ on adjacent carbon atoms, and any twoR² groups on adjacent carbon atoms, can cyclize to form a ring having3-8 ring atoms, which ring can be substituted and can be aromatic ornon-aromatic, and can contain a heteroatom selected from N, O and S as aring member; and any two of R¹ and R² on carbon atoms separated by asingle Nitrogen atom can cyclize to form a ring having 3-8 atoms, whichring can be substituted and can be aromatic or non-aromatic, and cancontain, in addition to the N between the carbon atoms to which linkedgroups are attached, an additional heteroatom selected from N, O and Sas a ring member; each m is independently 0 or 1; each n and p isindependently 0-2; L represents a three-atom linker corresponding to—C(R¹)_(p)—NR³—C(R¹)_(p)— or an optionally substituted pyridine-2,6-diylgroup; and M represents H or a metal cation; or a pharmaceuticallyacceptable salt thereof.
 19. The method of claim 18, wherein M is H. 20.The method of claim 19, wherein each R³ is H.
 21. The method of claim 1,wherein the compound of formula (1) has a structure selected from thegroup consisting of: